Nonpathogenesis of Simian Immunodeficiency Virus Infection Is Associated with Reduced Inflammation and Recruitment of Plasmacytoid Dendritic Cells to Lymph Nodes, Not to Lack of an Interferon Type I Response, during the Acute Phase

Campillo-Gimenez, Laure; Laforge, Mireille; Fay, Michèle; Brussel, Audrey; Cumont, Marie‐Christine; Monceaux, Valérie; Diop, Ousmane M.; Lévy, Yves; Hurtrel, Bruno; Zaunders, John; Corbeil, Jacques; Elbim, Carole; Estaquier, Jérǒme

doi:10.1128/jvi.01496-09

Cited by 54 publications

(70 citation statements)

References 50 publications

(70 reference statements)

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“…The finding of low AGM pDC CD4 expression is paradoxical, since CD4 is essential for HIV/SIV sensing by pDC and AGM pDC have been shown to efficiently sense SIVagm (7,12). Nonetheless, a lower level of production of IFN-I has been previously described during SIVagm infection in vivo (12,25). We wondered whether low pDC CD4 levels could have subtle effects on SIV sensing in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…We wondered whether low pDC CD4 levels could have subtle effects on SIV sensing in vivo. For instance, only sensing of infectious SIVagm particles has been previously investigated (12,25), while (i) most virions produced in vivo are noninfectious and (ii) sensing of virus-infected cells is more efficient in human and MAC (23). We stimulated peripheral blood mononuclear cells (PBMCs) of a large number of uninfected AGM and MAC with infectious SIV, using HSV as a control for CD4-independent sensing.…”

Section: Resultsmentioning

confidence: 99%

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Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection

Jochems

Jacquelin

Chauveau

et al. 2015

J Virol

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Human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/ SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4 ؉ T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. IMPORTANCEThe ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing. C hronic inflammation and immune activation in human immunodeficiency virus (HIV)-infected humans and in simian immunodeficiency virus (SIV)-infected macaques (MAC) lead to depletion of CD4ϩ T cells and progression to AIDS. Natural hosts of SIV, such as African green monkeys (AGM) and sooty mangabeys (SM), do not display chronic inflammation or AIDS (1). This is due to resolution of inflammation before the end of acute infection rather than to a lack of SIV recognition by the innate immune system (2). Natural hosts further differ from pathogenic HIV/SIV infections by exhibiting reduced infection rates in certain cell subsets, such as central memory CD4ϩ T cells (Tcm) (...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection

Jochems

Jacquelin

Chauveau

et al. 2015

J Virol

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“…However, this inflammatory response is downmodulated by the end of the acute phase of infection. Peak IFN-I levels have been found to be lower in the plasma and lymph node cells of SIV-infected AGMs than in MACs, indicating differences in IFN-I production between the two species in vivo (20,21). Nonetheless, exogenous injection of IFN-I at the peak of IFN-I production did not alter the ISG profile observed in AGMs (6).…”

mentioning

confidence: 85%

“…Blocking endosomal signaling decreased IFN-I levels and IA in treated immunological nonresponders (31). In acute SIV infections, pDCs are the main IFN-I-producing cells in lymph nodes (21,24,32).…”

mentioning

confidence: 99%

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Modulation of Type I Interferon-Associated Viral Sensing during Acute Simian Immunodeficiency Virus Infection in African Green Monkeys

Jochems

Petitjean

Kunkel

et al. 2015

J Virol

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Natural hosts of simian immunodeficiency virus (SIV), IMPORTANCEThe effects of HIV/SIV infections on the capacity of plasmacytoid dendritic cells (pDCs) to produce IFN-I in vivo are still incompletely defined. As IFN-I can restrict viral replication, contribute to inflammation, and influence immune responses, alteration of this capacity could impact the viral reservoir size. We observed that even in nonpathogenic SIV infection, the frequency of pDCs capable of efficiently sensing SIV and producing IFN-I was reduced during acute infection. We discovered that, concomitantly, cells other than pDCs had increased abilities for viral sensing. Our results suggest that pDC-produced IFN-I upregulates viral sensors in bystander cells, the latter gaining the capacity to produce IFN-I. These results indicate that in certain settings, cells other than pDCs can drive IFN-I-associated inflammation in SIV infection. This has important implications for the understanding of persistent inflammation and the establishment of viral reservoirs.

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Macrophage accumulation in gut mucosa differentiates AIDS from chronic SIV infection in rhesus macaques

2015

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Summary The relationship between recruitment of mononuclear phagocytes to lymphoid and gut tissues and disease in HIV and SIV infection remains unclear. To address this question, we did cross-sectional analyses of dendritic cell (DC) subsets and CD163+ macrophages in lymph nodes (LNs) and ileum of rhesus macaques with acute and chronic SIV infection and AIDS. In LNs significant differences were only evident when comparing uninfected and AIDS groups, with loss of myeloid DCs and CD103+ DCs from peripheral and mesenteric LNs, respectively, and accumulation of plasmacytoid DCs and macrophages in mesenteric LNs. In contrast, there were 4-fold more macrophages in ileum lamina propria in macaques with AIDS compared to chronic infection, and this increased to 40-fold in Peyer’s patches. Gut macrophages exceeded plasmacytoid DCs and CD103+ DCs by 10- to 17-fold in monkeys with AIDS but were at similar low frequencies as DCs in chronic infection. Gut macrophages in macaques with AIDS expressed IFN-α and TNF-α consistent with cell activation. CD163+ macrophages also accumulated in gut mucosa in acute infection but lacked expression of IFN-α and TNF-α. These data reveal a relationship between inflammatory macrophage accumulation in gut mucosa and disease and suggest a role for macrophages in AIDS pathogenesis.

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Nonpathogenesis of Simian Immunodeficiency Virus Infection Is Associated with Reduced Inflammation and Recruitment of Plasmacytoid Dendritic Cells to Lymph Nodes, Not to Lack of an Interferon Type I Response, during the Acute Phase

Cited by 54 publications

References 50 publications

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection

Modulation of Type I Interferon-Associated Viral Sensing during Acute Simian Immunodeficiency Virus Infection in African Green Monkeys

Macrophage accumulation in gut mucosa differentiates AIDS from chronic SIV infection in rhesus macaques

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